ES2581327T3 - Compound 2- (pyridin-2-yl) -1,7-diazaspiro [4.4] nonan-6-one as a modulator of voltage-dependent sodium ionotropic channels - Google Patents

Abstract

A compound of formula (I) that is 7-methyl-2- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] -1,7-diazaspiro [4.4] nonane-6-one: ** Formula ** or a pharmaceutically acceptable salt thereof.

Description

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DESCRIPTION

Compound 2- (pyridm-2-yl) -1,7-diazaspiro [4.4] nonan-6-one as a modulator of voltage-dependent sodium ionotrope channels

Field of the Invention

The invention relates to spiro derivatives, the use of said derivatives for the treatment of diseases and conditions mediated by the modulation of voltage-dependent sodium ionotrope channels, the compositions containing said derivatives and the procedures for their preparation.

Background of the invention

The voltage-dependent sodium ionotropic channels are responsible for the initial phase of the action potential, which is an electric depolarization wave that usually begins in the neuron soma and that propagates along the nerve axon towards the endings. In the terminations, the action potential triggers the entry of calcium and the release of neurotransmitters. For local anesthesia, drugs such as lidocafna are used, which block the voltage-dependent sodium ionotropic channels. Other sodium ionotropic channel blockers, such as lamotrigine and carbamazepine, are used to treat epilepsy. In the latter case, partial inhibition of voltage-dependent sodium ionotrope channels reduces neuronal excitability and reduces the spread of seizures. In the case of local anesthetics, the regional blockade of sodium ionotropic channels of sensory neurons prevents the conduction of painful stimuli. A key feature of these drugs is their mechanism dependent on the state of action. It is believed that the drugs stabilize an inactive conformation of the canal that is quickly adopted after the canal is opened. This inactive state provides a refractory period before the channel returns to its idle (closed) state ready to reactivate. As a result, state-dependent sodium ionotropic channel blockers inhibit the firing of neurons with a high frequency, for example, in response to painful stimuli, and will help prevent repetitive ignition during periods of prolonged neuronal depolarization that occurs. they could produce, for example, during a seizure. The action potentials triggered at low frequencies, for example, in the heart, will not be significantly affected by these drugs, although the safety margin differs in each case, since, at sufficiently high concentrations, each of these drugs is capable of blocking the states of rest or opening of the channels.

The family of voltage-dependent sodium ionotropic channels is made up of 10 subtypes, four of which are specific to the brain: NaV1.1, 1.2, 1.3 and 1.6. Of the other subtypes, NaV1.4 is found only in the skeletal muscle, NaV1.5 is specific to the heart muscle and NaV1.7, 1.8, and 1.9 are predominantly found in sensory neurons. The proposed fixation site for the state-dependent blockers of sodium ionotropic channels is highly conserved among all subtypes. As a result, drugs such as lidocafna, lamotrigine and carbamazepine are not able to differentiate subtypes. However, selectivity can be achieved as a result of the different frequencies in which the channels function normally.

Drugs that block the voltage-dependent sodium ionotropic channels in a state-dependent manner are also used for the treatment of bipolar disorder, either to reduce the symptoms of mania or depression, or as mood stabilizers for prevent the occurrence of instability episodes of mood. Clinical and preclinical tests also suggest that state-dependent sodium channel blockers may help reduce the symptoms of schizophrenia. For example, lamotrigine has been shown to reduce the symptoms of ketamine-induced psychosis in healthy human volunteers and, in addition, studies in patients suggest that the drug may increase the antipsychotic efficacy of some atypical antipsychotic drugs, such as Clozapine or olanzapine. It is proposed that the efficacy in these psychiatric disorders may result, in part, from a reduction in excess glutamate release. It is believed that the reduction of glutamate release is a consequence of the inhibition of the state-dependent sodium ionotropic channel in key areas of the brain, such as the frontal cortex. However, interaction with voltage-dependent calcium ionotrope channels can also contribute to the efficacy of these drugs.

International patent application WO 2007/042240 (Glaxo Group Limited) describes a series of quaternary derivatives of a-aminocarboxamide as modulators of voltage-dependent sodium ionotrope channels.

The object of the invention is to identify alternative compounds that modulate voltage-dependent sodium ionotrope channels.

Compendium of the invention

According to a first aspect of the invention, a compound of formula (I) is disclosed which is 7-methyl-2- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] -1.7 -diazaspiro [4.4] nonan-6-one:

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(I)

or a pharmaceutically acceptable salt or solvate thereof.

Detailed description of the invention

A reference to a compound of formula (I) and subgroups thereof also includes ionic forms, salts, solvates, isomers (including geometric and stereochemical isomers), tautomers, N-oxides and isotopes thereof, for example, as explain below; preferably, salts or tautomers or isomers or N-oxides or solvates thereof; and more preferably, the salts or the tautomers or the N-oxides or the solvates thereof, even more preferably, the salts or the tautomers or the solvates thereof. Henceforth, the compounds and their ionic forms, salts, solvates, isomers (among them the geometric and stereochemical isomers), tautomers, N-oxides and isotopes thereof, as defined in any aspect of the invention ( Except the intermediate compounds in the chemical processes) are called "compounds of the invention".

The compounds of formula (I) may exist in the form of salts, for example, salts by addition of acid or, in some cases, salts of organic and inorganic bases, such as carboxylate, sulphonate and phosphate salts. All of these salts are within the scope of this invention, and references to the compounds of formula (I) include the salt forms of the compounds.

The salts of the present invention can be synthesized from the parent compound containing a basic moiety by conventional chemical methods, such as the methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (editor), Camille G. Wermuth (editor), ISBN: 3-90639-026-8, hard paste, 388 pages, August 2002 .. Generally, such salts can be prepared by reacting the base forms of these compounds with the base or suitable acid in water or in an organic solvent, or in a mixture of both; In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are used.

Acid addition salts (monosal or disal) can be formed with a wide range of acids, both organic and inorganic. Examples of salts by acid addition include monosals or disals formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic acids (e.g., L-ascorbic), L- aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphorsulfonic, (+) - (1S) -campho-10-sulphonic, capric, caproic, capriflic, cinnamic, cfric, cyclic,

dodecylsulfuric, ethane-1,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumarole, galactaric, gentophic, glucoheptonic, D-gluconic, glucuronic (e.g., D-glucuronic), glutamic (e.g., L -glutamic), a- oxoglutaric, glycolic, hippuric, hydrohaluric (e.g., hydrobromic, hydrochloric, hydroiodic), isethionic, lactic (e.g., (+) - L-lactic, (±) -DL-lactic ), lactobionic, maleic, malico, (-) - L-malico, malonico, (±) -DL-mandelico, methanesulfonico, naftalen-2-sulfonico, naftalen-1,5-disulfonico, 1-hidroxi-2-naftoico, nicotfnico, nftrico, oleico, orotico, oxalico, palmftico, pamoico, fosforico, propionico, piruvico, L-pyroglutamic, salicflico, 4-amino-salicflico, sebacico, stearico, succfnico, sulfurico, tanico, (+) - L-tartaric, thiocyanic, p-toluenesulfonic, undecylene and valeric, as well as acylated amino acids and cation exchange resins.

A specific group of salts consists of the salts formed from acetic, hydrochloric, iodhydric, phosphoric, nitric, sulfuric, cfric, lactic, succinic, maleic, malicic, isethionic, smoking, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylaphonic), ethane sulfide , naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic. A particular salt is the hydrochloride salt. Another particular salt is the hydrogen sulfate salt, also known as a hemisulfate salt.

When the compounds of formula (I) contain an amine function, they can form quaternary ammonium salts, for example, by reacting with an alkylating agent according to methods well known to those skilled in the art. Such quaternary ammonium compounds are within the scope of formula (I).

The compounds of the invention may exist as monosal or disal according to the pKa of the acid from which the salt is formed.

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The salt forms of the compounds of the invention are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are explained in Berge et al., 1977, "Pharmaceutically Acceptable Salts", J. Pharm. Sci., Vol. 66, pages 1-19. However, salts that are not pharmaceutically acceptable can also be prepared as intermediate forms that can then be converted into pharmaceutically acceptable salts. Such forms of non-pharmaceutically acceptable salts, which may be useful, for example, for the purification or separation of the compounds of the invention, also form part of the invention.

In one embodiment, the compound of formula (I) is:

(2R, 5S) -7-methyl-2- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] -1,7-diazaspiro [4.4] nonan-6-one (E1) hydrochloride (E1). In an alternative embodiment, the compound of formula (I) is:

(2S, 5S) -7-methyl-2- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] -1,7-diazaspiro [4.4] nonan-6-one (E3) hydrochloride (E3).

Those skilled in the art of organic chemistry will appreciate that many organic compounds may complex with the solvents in which they are reacted or from which they precipitate or crystallize. These complexes are known as "solvates." For example, a complex with water is known as a "hydrate." Pharmaceutically acceptable solvates of the compound of the invention are within the scope of the invention. In one embodiment, the pharmaceutically acceptable solvates of the compounds of the invention include the hydrate thereof. In a further embodiment, the compound of formula (I) is:

(2R, 5S) -7-methyl-2- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] -1,7-diazaspiro [4.4] nonan-6-one (E2) hemisulfate hydrate.

Compounds of the formula (I) that contain an amine function can also form N-oxides. A reference herein to a compound of formula (I) that contains an amine function also includes the N-oxide.

When a compound contains several amine functions, one or more of a nitrogen atom can be oxidized to form an N-oxide. Concrete examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.

The N-oxides can be formed by treating the corresponding amine with an oxidizing agent, such as hydrogen peroxide, or a peracid (eg, a peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, by Jerry March , 4th edition, Wiley Interscience, pages. More particularly, the N-oxides can be manufactured by the method of LW Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with the m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent, such as dichloromethane.

Polymorphs thereof are also included within the scope of the compound and of the different salts of the invention.

The compounds of the formula (I) may exist in numerous different forms of geometric and tautomeric isomers, and references to the compounds of formula (I) include all of these forms. For the avoidance of doubt, when a compound may exist in one of the different forms of geometric or tautomeric isomers and only one is specifically described or shown, all the others are, however, encompassed by formula (I).

In one embodiment, the invention discloses compounds of any of formulas (Ia) - (Id):

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(Ic); or

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In another embodiment, the invention discloses compounds of formula (la). Representative examples of the compounds of formula (Ia) include examples 1 and 2 described herein.

In an alternative embodiment, the invention discloses compounds of formula (lb). Representative examples of the compounds of formula (lb) include example 3 described herein.

The present invention includes all isotopically labeled compounds that are pharmaceutically acceptable of the invention, namely, the compounds of the formula (I), wherein one or more atoms are replaced by atoms having the same atomic number, but a mass Atomic or mass number different from the atomic mass or mass number that is usually found in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention comprise hydrogen isotopes, such as 2H (D) and 3H (T), carbon such as ace 11C, 13C and 14C, fluorine, such as 18F, nitrogen, such 15 as 13N and 15N, oxygen, such as 15O, 17O and 188.

Some compounds of formula (I) labeled with isotopes, for example, those incorporating a radioactive isotope, are useful for studies of substrate and / or drug distribution by tissues. The compounds of formula (I) can also have valuable diagnostic properties when they can be used to detect or identify the formation of a complex between a labeled compound and other molecules, peptides, proteins, enzymes or receptors. The detection or identification methods may use compounds that are labeled with labeling agents, such as radioisotopes, enzymes, fluorescent substances, luminous substances (e.g., luminol, derivatives of luminol, luciferin, ecuorine and luciferase) etc. Tritium radioactive isotopes, namely 3H (T), and carbon 14, namely 14C, are particularly useful for this purpose in view of how easy their incorporation is and how easy their detection is.

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Substitution with heavier isotopes, such as deuterium, namely 2H (D), may provide some therapeutic advantages that are the result of greater metabolic stability, for example, the increase in half-life in vivo or the reduction in the necessary dose. and, thus, may be preferred in some circumstances.

11 1 Q 1C H

Substitution with positron emitting isotopes, such as C, F, O, and N, may be useful for positron emission tomography (PET) studies when exploring target occupancy.

The isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the examples and accompanying preparations by using the appropriate isotope-labeled reactants instead. of the unmarked reactant previously used.

In accordance with one more aspect of the invention, a process for preparing a compound of formula (I) as defined herein is disclosed, comprising:

(a) reacting a compound of formula (II):

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or a protected derivative thereof, wherein L1 represents a suitable leaving group, such as a halogen atom (e.g., bromine) or a -O-SO2CF3 group, with a compound of formula (III):

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wherein X represents boronic acid;

(b) reduction of a compound of formula (IV):

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or a protected derivative thereof;

(c) deprotection of a protected derivative of a compound of formula (I);

(d) optional formation of a pharmaceutically acceptable salt of a compound of formula (I).

When L1 represents a group -O-SO2CF3, the process (a) typically comprises a Suzuki coupling reaction in the presence of a suitable catalyst, such as a palladium catalyst, and a suitable base, such as potassium carbonate, in a suitable solvent, such as 1,4-dioxane.

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When L1 represents a halogen atom, such as bromine, the process (a) typically comprises a Suzuki coupling reaction in the presence of a suitable catalyst, such as palladium tetrakis-triphenylphosphine, and an ideal base. It is recognized that alternative aryl coupling protocols can be used instead of a Suzuki reaction, for example, a Stille coupling.

The process (b) typically comprises the use of suitable reducers, such as sodium triacetoxyborohydride, in the presence of an ideal acid (such as HCl), borane or a modified borane, such as a tertiary butylamine complex: borane, or hydrogenation on a suitable catalyst, such as platinum.

The compounds of formula (II) can be prepared according to scheme 1:

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wherein L1 represents a suitable leaving group, such as a halogen atom (e.g., bromine), or a group -O-SO2-CF3.

Step (i) typically comprises the condensation of a compound of formula (V) with a suitable carboxydehyde compound in the presence of a dehydration agent, such as magnesium sulfate, in a solvent, such as dichloromethane.

Step (ii) typically comprises a cycloaddition reaction [3 + 2] with phenylvinylsulfone catalyzed by a transition metal salt, such as a copper or silver salt (eg, silver acetate) or an acid of Lewis (such as calcium triflate), typically in the presence of a base and, optionally, a chiral phosphine ligand, such as 1- (di (1-naphtenyl) phosphinyl) -2 - ((4S) -4- (propan -2-yl) -4,5-dihydro-1,3-oxazolyl) -ferrocene.

Step (iii) typically comprises the removal of phenyl sulfone with a strong base, such as potassium ferf-butoxide.

Step (iv) typically comprises the reduction of the imine with the use of a hydride donor, such as sodium borohydride or sodium triacetoxyborohydride, in the presence of a suitable acid (such as HCl), borane or a modified borane (such as a tertiary butylamine complex: borane), or hydrogenation on a suitable catalyst, such as platinum.

The compounds of formula (IV) can be prepared according to scheme 2:

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where P1 and P2 represent suitable nitrogen protecting groups.

Step (i) comprises the N-protection of the amino group of the amide (V) by reacting it, for example, with an imine, such as benzophenone imine, in a suitable solvent, such as DCE.

Step (ii) comprises the reaction with a propargilation agent, such as propargyl bromide, in the presence of a base, such as potassium ferf-butoxide, in a suitable solvent, such as THF.

Step (iii) comprises the removal of the N-protective group that can typically be achieved by treatment with a mild acid (such as citric acid) in a suitable solvent, such as THF.

Step (iv) comprises a chiral resolution step, in which the amine (XI) is formed in a chiral salt by fractional crystallization of a solution with a chiral acid (eg acid (2S) -2- (6 -methoxy-2- naphthyl) propanoic acid or (+) - mandelic acid) from a suitable solvent (for example, acetonitrile, THF or IPA), followed

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of the release of the resolved amine by treatment with a base, such as a basic ion exchange resin.

Step (v) comprises the protection of amino nitrogen, which can be achieved, for example, by the introduction of a Boc group by treatment of the amine with the Boc anhydride.

Step (vi) comprises the conversion of a substituted 2-chloropyridine into the 2-iodopyridine that could typically be achieved by treatment with concentrated aqueous HI solution or by using sodium iodide in acetyl chloride.

Step (vii) comprises a Sonogashira coupling that typically uses a copper catalyst, such as copper iodide, a palladium catalyst (for example, PdCh (Ph3P) 2) and often includes an amine base, such as diethylamine or diisopropylamine, in a suitable solvent, such as THF, DCE, acetonitrile or dimethyl tert-butyl ether.

The step (viii) is an acid catalyzed deprotection step that is typically achieved by treatment with trifluoroacetic acid, formic acid or sulfuric acid in a suitable solvent, such as dichloromethane, 1,4-dioxane, THF or water.

Step (ix) is typically achieved by treatment with a silver or gold salt, such as silver triflate, in a solvent such as acetonitrile.

The compounds of formula (III), (V) and (XIV) are either known, or they can be prepared according to known methodologies.

The experts in organic synthesis will appreciate that two or more chemical stages of the above schemes can be executed sequentially without the isolation of the intermediate materials.

It can also be recognized that the separation of the isomers can occur at any suitable stage in the synthesis sequence. It should be emphasized that such chiral separation forms a key aspect of the invention and that such separation can be performed in accordance with the methodology described herein, or can be performed in accordance with the known methodology. It is also recognized that it may be beneficial to temporarily form a protected derivative of a synthesis intermediate, for example, a Boc-protected amine, to facilitate chromatographic separation, chiral resolution, or to improve solubility or improve the yield of certain stages

In many of the reactions described above, it may be necessary to protect one or more groups to prevent the reaction from taking place at an undesirable location of the molecule. Examples of protective groups and methods for protecting and deprotecting functional groups can be found in Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd edition; John Wiley and Sons, 1999).

An aldehyde or ketone group may be protected, for example, as an acetal (R-CH (OR) 2) or ketal (R2C (OR) 2), respectively, in which the carbonyl group (> C = O) is treated with, for example, a primary alcohol. Alternatively, the aldehyde or ketone group is easily regenerated by hydrolysis with excess water in the presence of acid.

An amine group may be protected, for example, as an amide (-NRCO-R) or a carbamate (-NRCO-OR), for example, as: a methylamide (-NHCO-CH3); a benzyl carbamate (-NHCO-OCH2C6H5, -NH-Cbz or NH-Z); as a t-butyl carbamate (-NHCO-oC (CH3) 3, -NH-Boc); a 2-biphenyl-2-propyl carbamate (-NHCO-OC (CH3) 2C6H4C6H5, -NH-Boc), such as a 9-fluorenylmethyl carbamate (-NH-Fmoc), such as a 6- nitroveratryl carbamate (-NH -Nvoc), as a 2-trimethylsilylethyl carbamate (-NH-Teoc), as a 2,2,2-trichloroethyl carbamate (-NH-Troc), as an allyl carbamate (-NH-Alloc) or as a 2 (-phenylsulfonyl) ethyl carbamate (-NH-Psec).

Other protecting groups for amines, such as cyclic amines and heterocyclic NH groups, include toluenesulfonyl (tosyl) and methanesulfonyl (mesyl) groups, benzyl groups such as a para-methoxybenzyl (PMB) group, and tetrahydropyranyl (THP) groups .

In addition, amines may be protected as imines, including benzylimines and substituted benzhydryrimines.

As explained above, it is believed that the compounds of the invention may be useful for the treatment of diseases and conditions mediated by the modulation of voltage-dependent sodium ionotrope channels.

In one embodiment, the compounds will be state-dependent sodium ionotropic channel inhibitors.

In another embodiment, the compounds will be inhibitors dependent on the state of the sodium ionotrope channel selective of the NaV1.7 subtype.

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In another embodiment, the compounds will be state-dependent sodium ionotropic channel inhibitors that have a developmental capacity profile suitable for oral administration, for example, in terms of exposure (Cmax) and / or bioavailability.

In one embodiment, the compounds will be inhibitors of the sodium ionotropic channel.

In another embodiment, the compounds will be inhibitors of the sodium ionotropic channel of the NaV1.7 subtype selective.

In another embodiment, the compounds will be sodium channel inhibitors that have a developmental capacity profile suitable for oral administration, for example, in terms of exposure (Cmax) and / or bioavailability.

According to another aspect of the invention, compounds of the invention are disclosed for use as a medicament, preferably a medicament for humans.

According to one more aspect, the invention discloses the use of compounds of the invention for the manufacture of a medicament for the treatment or prevention of a disease or condition mediated by the modulation of voltage-dependent sodium channels.

In a specific embodiment, the compounds of the invention can be useful as analgesics. For example, they may be useful for the treatment of chronic inflammatory pain (eg, pain associated with rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis); musculoskeletal pain; low back pain and neck pain; sprains and strains; neuropathic pain; pain maintained by the sympathetic system; myositis; pain associated with cancer and fibromyalgia; pain associated with migraine; pain associated with the flu and other African infections, such as the common cold; rheumatic fever; pain associated with functional bowel disorders, such as non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome; pain associated with myocardial ischemia; postoperative pain; headache; odontalgia; and dysmenorrhea.

The compounds of the invention can be useful for the treatment of neuropathic pain. Neuropathic pain syndromes may develop after neuronal injury and the resulting pain may persist for months or years, even after the original injury has healed. Neural injury can occur in the peripheral nerves, dorsal roots, spinal cord or certain regions of the brain. Neuropathic pain syndromes are traditionally classified according to the disease or event that precipitated them. Neuropathic pain syndromes include: diabetic neuropathy; sciatica; non-specific low back pain; multiple sclerosis pain; fibromyalgia; HIV-related neuropathy; postherpetic neuralgia; trigeminal neuralgia; and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions. These conditions are difficult to treat and although it is known that several drugs have very little efficacy, complete pain control is rarely achieved. Symptoms of neuropathic pain are incredibly heterogeneous and are often described as glowing and tearing spontaneous pain, or ongoing burning pain. In addition, there is pain associated with sensations that are not usually painful, such as "tingling" (paraesthesia and dysesthesia), increased sensitivity with palpation (hyperesthesia), painful sensation after innocuous stimulation (dynamic, static or thermal allodynia ), increased sensitivity to harmful stimuli (heat hyperalgesia, cold, mechanical), sensation of continuous pain after withdrawal of stimulation (hyperpathy) or an absence or deficit in certain sensory pathways (hypoalgesia).

The compounds of the invention can also be useful for improving inflammatory disorders, for example, for the treatment of skin conditions (eg, sunburn, burns, eczema, dermatitis, psoriasis); ophthalmic diseases; lung diseases (eg, asthma, bronchitis, emphysema, allergic rhinitis, non-allergic rhinitis, cough, respiratory failure syndrome, poultry pneumopathy, allergic alveolitis, chronic obstructive pulmonary disease (COPD); digestive tract disorders (e.g. eg, Crohn's disease, ulcerative colitis, celiac disease, regional ileitis, irritable bowel syndrome, inflammatory enteropathies, gastroesophageal reflux); other conditions with an inflammatory component, such as migraine, multiple sclerosis and myocardial ischemia.

In one embodiment, the compounds of the invention are useful for the treatment of neuropathic pain or inflammatory pain, as described herein.

Without wishing to commit to the theory, other diseases or conditions that may be mediated by the modulation of the voltage-dependent sodium ionotropic channels are selected from the list consisting of [numbers in parentheses after the diseases listed below refer to classification code in Diagnostic and Statistical Manual of Mental Disorders, 4th edition, published by the American Psychiatric Association (DSM-IV) and / or the International Classification of Diseases, 10th edition (ICD-10)]:

i) Depression and mood disorders, including major depressive episode, manic episode, mixed episode and hypomanic episode; depressive disorders that include major depressive disorder, dysthymic disorder (300.4), unspecified depressive disorder (311); Bipolar disorders that include bipolar I disorder, bipolar II disorder (recurrent major depressive episodes with hypomanic episodes) (296.89), cyclothmic disorder (301.13) and unspecified bipolar disorder (296.80); other mood disorders that include mood disorder due to a general medical illness (293.83) (which includes subtypes with depressive symptoms, with an episode similar to major depressive, with manic symptoms and with mixed symptoms), disorder of the

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Substance-induced mood (including subtypes with depressive symptoms, with manic symptoms and with mixed symptoms) and mood disorder not specified (296.90);

ii) Schizophrenia, which includes the subtypes of the paranoid type (295.30), of the disorganized type (295.10), of the catatonic type (295.20), of the undifferentiated type (295.90) and of the residual type (295.60); schizophreniform disorder (295.40); schizoaffective disorder (295.70) that includes bipolar and depressive type subtypes; delusional disorder (297.1) that includes subtypes of the erotomanfac type, delusional type of greatness, celotypy, persecutory type, somatic type, mixed type and unspecified type; brief psychotic disorder (298.8); shared psychotic disorder (297.3); psychotic disorder due to a generalized medical illness that includes subtypes with delusions and hallucinations; substance-induced psychotic disorder, which includes subtypes with delusions (293.81) and hallucinations (293.82); and unspecified psychotic disorder (298.9).

iii) Anxiety disorders among them the crisis of anguish; distress disorder that includes distress disorder without agoraphobia (300.01) and distress disorder with agoraphobia (300.21); agoraphobia; agoraphobia without history of distress disorder (300.22), specific phobia (300.29, formerly simple phobia) that includes the animal type subtypes, environmental type, blood-injections-damage type, situational type and other types), social phobia (social anxiety disorder (300.23), obsessive-compulsive disorder (300.3), post-traumatic stress disorder (309.81), acute stress disorder (308.3), generalized anxiety disorder (300.02), anxiety disorder due to general medical illness ( 293.84), substance-induced anxiety disorder, separation anxiety disorder (309.21), anxiety adjustment disorder (309.24) and unspecified anxiety disorder (300.00).

iv) Substance-related disorders, which include substance use disorders such as substance dependence, compulsive desire for substances and substance abuse; substance-induced disorders such as substance intoxication, substance withdrawal, substance-induced delirium, substance-induced persistent dementia, substance-induced persistent amnesic disorder, substance-induced psychotic disorder, substance-induced mood disorder, anxiety disorder substance-induced, substance-induced sexual dysfunction, substance-induced sleep disorder and persistent hallucinogenic perception disorder (flashbacks); alcohol-related disorders such as alcohol dependence (303.90), alcohol abuse (305.00), alcohol intoxication (303.00), alcohol withdrawal (291.81), alcohol intoxication delirium, alcohol withdrawal delirium, induced persistent dementia by alcohol, alcohol-induced persistent amnesic disorder, alcohol-induced psychotic disorder, alcohol-induced mood disorder, alcohol-induced anxiety state disorder, alcohol-induced sexual dysfunction, alcohol-induced sleep disorder and alcohol-related disorder unspecified alcohol (291.9); disorders related to amphetamines (or amphetamine-like substances) such as amphetamine dependence (304.40), amphetamine addiction (305.70), amphetamine poisoning

(292.89), amphetamine withdrawal (292.0), amphetamine intoxication delirium, amphetamine-induced psychotic disorder, amphetamine-induced mood disorder, amphetamine-induced anxiety disorder, amphetamine-induced sexual dysfunction, sleep-induced sexual disorder amphetamine and amphetamine-related disorder not specified (292.9); Caffeine-related disorders such as coffee poisoning

(305.90), coffee-induced anxiety disorder, coffee-induced sleep disorder and unspecified coffee-related disorder (292.9); cannabis-related disorders, such as cannabis dependence (304.30), cannabis abuse (305.20), cannabis poisoning (292.89), cannabis intoxication delirium, cannabis-induced psychotic disorder, cannabis-induced anxiety disorder and related disorder with unspecified cannabis (292.9); Cocaine-related disorders, such as cocaine dependence (304.20), cocaine abuse (305.60), cocaine poisoning (292.89), cocaine withdrawal (292.0), cocaine poisoning delirium, cocaine-induced psychotic disorder, cocaine disorder cocaine-induced mood, cocaine-induced anxiety disorder, cocaine-induced sexual dysfunction, cocaine-induced sleep disorder, and unspecified cocaine-related disorder (292.9); hallucinogen-related disorders, such as hallucinogen dependence (304.50), hallucinogen abuse (305.30), hallucinogen poisoning (292.89), persistent hallucinogen perceptual disorder (retrospective scenes) (292.89), hallucinogen poisoning delirium, psychotic disorder hallucinogen-induced, hallucinogen-induced mood disorder, hallucinogen-induced anxiety disorder and hallucinogen-related disorder not specified (292.9); inhalant-related disorders such as dependence on inhalants (304.60), abuse of inhalants (305.90), inhalation poisoning (292.89), delirium from inhalation poisoning, persistent inhaler-induced dementia, inhalant-induced psychotic disorder, state disorder Inhalant-induced mood, inhaler-induced anxiety disorder, and unspecified inhalant-related disorder (292.9); Nicotine-related disorders such as nicotine dependence (305.1), nicotine withdrawal (292.0) and nonspecine-related disorder not specified (292.9); Opioid-related disorders, such as opioid dependence (304.00), opioid abuse (305.50), opioid poisoning (292.89), opioid withdrawal (292.0), opioid intoxication delirium, opioid-induced psychotic disorder, opioid disorder opioid-induced mood, opioid-induced sexual dysfunction, opioid-induced sleep disorder and opioid-related disorder not specified (292.9); disorders related to phencyclidine (or analogs of phencyclidine) such as dependence on phencyclidine (304.60), abuse of phencyclidine (305.90), poisoning by phencyclidine (292.89), delirium from poisoning by phencyclidine, psychotic disorder induced by phencyclidine disorder mood induced

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Phencyclidine, Phencyclidine-induced anxiety disorder and unspecified Phencyclidine-related disorder

(292.9); sedative, hypnotic or anxiolytic related disorders, such as sedative, hypnotic or anxiolytic dependence (304.10), sedative, hypnotic or anxiolytic abuse (305.40), sedative, hypnotic or anxiolytic poisoning (292.89), sedative, hypnotic withdrawal or anxiolytics (292.0), delirium from sedative, hypnotic or anxiolytic poisoning, delirium from sedative, hypnotic or anxiolytic withdrawal, persistent sedative, hypnotic or anxiolytic dementia, persistent sedative, hypnotic or anxiolytic amnesic disorder, psychotic silk induced disorder , hypnotic or anxiolytic, sedative, hypnotic or anxiolytic-induced mood disorder, sedative, hypnotic or anxiolytic-induced anxiety disorder, sedative, hypnotic or anxiolytic-induced sexual dysfunction, sedative-induced, hypnotic or anxiolytic sleep disorder, and disorder related to sedatives, hypnotics or ansiolf Ticos not specified

(292.9); disorder related to several substances such as dependence on several substances (304.80); and disorders related to other (or unknown) substances such as anabolic steroids, nitrate inhalers and nitrous oxide.

v) Cognitive improvement, including the treatment of cognitive impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic diseases associated with cognitive impairment, p. eg Alzheimer's disease:

vi) Sleep disorders, including primary sleep disorders such as dysomnias such as primary insomnia (307.42), primary hypersomnia (307.44), narcolepsy (347), sleep disorder related to breathing (780.59), circadian rhythm disorder of sleep (307.45) and unspecified dysomnia (307.47); primary sleep disorders such as parasomnios such as nightmares (307.47), night terrors (307.46), sleepwalking (307.46) and unspecified parasomnia (307.47); sleep disorders related to another mental disorder such as insomnia related to another mental disorder (307.42) and hypersomnia related to another mental disorder (307.44); sleep disorders due to a general medical condition, in particular sleep disorders associated with neurological disorders, neuropathic pain, restless legs syndrome, heart and lung diseases; and substance-induced sleep disorder that includes subtypes of insomnia, hypersomnia, parasomnia and mixed type; Sleep apnea and time lag syndrome:

vii) Eating disorders such as anorexia nervosa (307.1) including the subtypes of the restrictive type and the compulsive / purgative atracon type; bulimia nervosa (307.51) which includes the subtypes of the purgative and non-purgative types; obesity; binge eating disorder; atracon eating disorder; and unspecified eating disorder (307.50):

viii) Autism spectrum disorders, including autistic disorder (299.00), Asperger disorder (299.80), Rett disorder (299.80), childhood disintegrative disorder (299.10), and generalized unspecified developmental disorder (299.80, which includes atypical autism ).

ix) Attention deficit disorder and disturbing behavior, which includes the subtypes combined type of attention deficit hyperactivity disorder (314.01), type with attention deficit disorder of attention deficit hyperactivity disorder (314.00), type with hyperactive predominance - impulsiveness of attention deficit hyperactivity disorder (314.01) and attention deficit disorder with unspecified hyperactivity (314.9); hyperkinetic disorder; disruptive behavior disorders such as behavioral disorder that includes the subtypes of childhood onset (321.81), onset of adolescence (312.82) and unspecified onset (312.89), challenging negativist disorder (313.81) and disturbing behavior disorder not specified; and tic disorders and Tourette disorder (307.23):

x) Personality disorders including subtypes paranoid personality disorder (301.0), schizoid personality disorder (301.20), schizotopic personality disorder (301.22), antisocial personality disorder (301.7), borderline personality disorder ( 301.83), histrionic personality disorder (301.50), narcissistic personality disorder (301.81), avoidance personality disorder (301.82), dependency personality disorder (301.6), obsessive-compulsive personality disorder (301.4 ) and unspecified personality disorder (301.9): and

xi) Sexual dysfunctions, which include sexual desire disorders such as hypoactive sexual desire disorder (302.71) and sex aversion disorder (302.79); disorders of sexual arousal, such as sexual arousal disorder in women (302.72) and erection disorder in men (302.72); orgasmic disorders, such as female orgasmic disorder (302.73), male orgasmic disorder (302.74) and premature ejaculation (302.75); sexual pain disorders, such as dyspareunia (302.76) and vaginismus (306.51); unspecified sexual dysfunction (302.70); paraphilias, such as exhibitionism (302.4), fetishism (302.81), frotism or photteurism (302.89), pedophilia (302.2), sexual masochism (302.83), sexual sadism (302.84), transvestist fetishism (302.3), voyeurism (302.82) and paraphilia not specified (302.9); sexual identity disorders, such as sexual identity disorder in children (302.6) and sexual identity disorder in adolescents or adults (302.85); and unspecified sexual disorder (302.9).

xii) Impulse control disorder, which includes: intermittent explosive disorder (312.34), kleptomania (312.32), pathological play (312.31), pyromania (312.33), trichotillomanfa (312.39), impulse control disorder

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not specified (312.3), compulsive feeding, compulsive shopping, compulsive sexual behavior and compulsive accumulation.

In another embodiment, the diseases or conditions that may be mediated by the modulation of the voltage-dependent sodium ionotropic channels are depression or mood disorders.

In another embodiment, the diseases or conditions that may be mediated by the modulation of voltage-dependent sodium ionotrope channels are substance-related disorders.

In another embodiment, the diseases or conditions that may be mediated by the modulation of the voltage-dependent sodium ionotropic channels are bipolar disorders (bipolar disorder I, bipolar disorder II (ie, recurrent major depressive episodes with hypomanic episodes) (296.89 ), cyclothmic disorder (301.13) or unspecified bipolar disorder (296.80)).

In yet another embodiment, the diseases or conditions that may be mediated by the modulation of voltage-dependent sodium ionotrope channels are nicotine-related disorders, such as nicotine dependence (305.1), nicotine withdrawal (292.0) or disorder related to unspecified nicotine (292.9).

The compounds of the invention can also be useful for the treatment and / or prevention of treatable and / or preventable disorders with anticonvulsants, such as epilepsy, which includes posttraumatic epilepsy, obsessive compulsive disorders (OCT), sleep disorders (which includes circadian rhythm disorders, insomnia and narcolepsy), tics (eg, Giles de la Tourette syndrome), ataxias, muscle stiffness (spasticity) and temporomandibular joint dysfunction.

The compounds of the invention can also be useful for the treatment of bladder hyperrelexia after inflammation of the bladder.

The compounds of the invention can also be useful for the treatment of neurodegenerative and neurodegeneration diseases, such as dementia, in particular degenerative dementia (which includes senile dementia, Alzheimer's disease, Pick's disease, Huntington's chorea, Parkinson's disease and Creutzfeldt-Jakob disease, motor neuron disease). The compounds may also be useful for the treatment of amyotrophic lateral sclerosis (ALS) and neuroinflammation.

The compounds of the invention can also be useful for neuroprotection and for the treatment of neurodegeneration after stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like.

The compounds of the invention can also be useful for the treatment of tinnitus and as local anesthetics.

The compounds of the invention can also be used in combination with other therapeutic agents. Also described herein is a combination comprising a compound of the invention or a pharmaceutically acceptable derivative thereof, together with another therapeutic agent.

When a compound of the invention or a pharmaceutically acceptable derivative thereof is used in polytherapy with a second therapeutic agent active against the same disease, the dose of each compound may differ from that used when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. It will be appreciated that the amount of a compound of the invention that is needed to be used for treatment will vary with the nature of the condition to be treated and with the age and condition of the patient, and will ultimately be at the discretion of the attending physician or veterinarian. .

The combinations mentioned above may be presented for convenience to be used in the form of a pharmaceutical formulation and, therefore, pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient, comprise a additional aspect of the invention. The individual components of said combinations can be administered sequentially or simultaneously in independent pharmaceutical formulations or in polytherapy by any suitable route.

When administration is sequential, both the compound of the invention and the second therapeutic agent can be administered first. When the administration is simultaneous, the combination can be administered in the same pharmaceutical composition or in a different one.

When combined in the same formulation, it will be appreciated that two compounds must be stable and compatible with each other and with the other components of the formulation. When formulated separately, they can be provided in any convenient formulation, with the comfort known to such compounds in the art. When used for the treatment or prophylaxis of pain, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be used in combination with other medications indicated as being useful for the

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treatment or prophylaxis of pain of neuropathic origin, which includes neuralgia, neuritis and low back pain, and for inflammatory pain that includes osteoarthritis, rheumatoid arthritis, acute inflammatory pain, low back pain and migraine. Such therapeutic agents include, for example, COX-2 inhibitors (cyclooxygenase 2), such as celecoxib, deracoxib, rofecoxib, valdecoxib, parecoxib, COX-189 or 2- (4-ethoxyphenyl) -3- (4-methanesulfonylphenyl) ) -pyrazolo [1,5-b] pyridazine (international patent application WO 99/012930); 5-lipoxygenase inhibitors; NSAIDs (non-steroidal anti-inflammatory drugs), such as diclofenac, indomethacin, nabumetone or ibuprofen; bisphosphonatates, leukotriene receptor antagonists; FARME (disease modifying anti-rheumatic drugs), such as methotrexate; adenosine A1 receptor agonists; sodium ionotropic channel blockers, such as lamotrigine; nMdA (N-methyl-D-aspartate) modulators, such as glycine or memantine receptor antagonists; ligands for the a2§ subunit of the voltage-dependent calcium ionotropic channels, such as gabapentin, pregabalin and solzira; tricyclic antidepressants such as amitriptyline; antiepileptics stabilizing neurons; cholinesterase inhibitors, such as galantamine; monoaminergic uptake inhibitors, such as venlafaxine; opioid analgesics; local anesthetics; 5HT1 agonists, such as triptans, for example, sumatriptan, naratriptan, zolmitriptan, eletriptan, frovatriptan, almotriptan or rizatriptan; nicotinic acetylcholine receptor modulators (nACh); glutamate receptor modulators, for example, NR2B subtype modulators; EP4 receptor ligands; EP2 receptor ligands; EP3 receptor ligands; EP4 agonists and EP2 agonists; EP4 antagonists; EP2 antagonists and EP3 antagonists; cannabinoid receptor ligands; bradykinin receptor ligands; vanilloid receptor or transient receptor potential ligands (TRP); and purinergic receptor ligands, including antagonists in P2X3, P2X2 / 3, P2X4, P2X7 or P2X4 / 7; KCNQ / Kv7 channel openers, such as retigabine; Other COX-2 inhibitors are described in US Pat. UU. 5,474,995, 5,633,272, 5,466,823, 6,310,099 and 6,291,523; and in international patent applications WO 96/25405, WO 97/38986, WO 98/03484, WO 97/14691, WO 99/12930, WO 00/26216, WO 00/52008, WO 00/38311, WO 01 / 58881 and WO 02/18374.

The compounds of the invention can be used in combination with the following agents to treat or prevent psychotic disorders: i) antipsychotics; ii) drugs for extrapyramidal side effects, for example, anticholinergics (such as benzatropin, biperidene, procyclidine and trihexyphenyl), antihistamines (such as diphenhydramine) and dopamine drugs (such as amantadine); iii) antidepressants; iv) anxiolytics; and v) cognitive enhancers, for example, cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine).

The compounds of the invention can be used in combination with the following agents to treat or prevent psychotic disorders: i) antipsychotics; ii) drugs for extrapyramidal side effects, for example, anticholinergics (such as benzatropin, biperidene, procyclidine and trihexyphenyl), antihistamines (such as diphenhydramine) and dopamine drugs (such as amantadine); iii) antidepressants; iv) anxiolytics; and v) cognitive enhancers, for example, cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine).

The compounds of the invention can be used in combination with antidepressants to treat or prevent depression and mood disorders:

The compounds of the invention can be used in combination with the following agents to treat or prevent bipolar disease: i) mood stabilizers; ii) antipsychotics; and iii) antidepressants.

The compounds of the invention can be used in combination with the following agents to treat or prevent anxiety disorders: i) anxiolytics; and ii) antidepressants.

The compounds of the invention can be used in combination with the following agents to improve nicotine withdrawal and reduce the compulsive desire for nicotine: i) nicotine replacement therapy, for example, a sublingual formulation of nicotine p-cyclodextrin and nicotine patches; and ii) bupropion.

The compounds of the invention can be used in combination with the following agents to improve the

alcohol withdrawal and reduce the compulsive desire of alcohol: i) NMDa receptor antagonists, by

example, acamprosate; ii) GABA receptor agonists, for example, tetrabamate; and iii) opioid receptor antagonists, for example, naltrexone.

The compounds of the invention can be used in combination with the following agents to improve the

withdrawal from opiates and reduce compulsive desire for opiates: i) opioid receptor agonist for antagonist

of opioid receptor k, for example, buprenorphine; ii) opioid receptor antagonists, for example, naltrexone; and iii) vasodilator antihypertensives, for example, lofexidine.

The compounds of the invention can be used in combination with the following agents to treat or prevent sleep disorders: i) benzodiazepines, for example, temazepam, lormetazepam, estazolam and triazolam; ii) non-benzodiazepine hypnotics, for example, zolpidem, zopiclone, zaleplon and indiplon; iii) barbiturates, for example, approve bital, butabarbital, pentobarbital, secobarbital and phenobarbital; iv) antidepressants; v) other sedative hypnotics, for example, chloral hydrate and chlormethiazole.

The compounds of the invention can be used in combination with the following drugs to treat anorexia: i) appetite stimulants, for example, cyproheptidine; ii) antidepressants; iii) antipsychotics; iv) zinc; and v) premenstrual drugs, for example, pyridoxine and progesterones.

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The compounds of the invention can be used in combination with the following agents to treat or prevent bulimia: i) antidepressants; ii) opioid receptor antagonists; iii) antiemetics, for example ondansetron; iv) testosterone receptor antagonists, for example, flutamide; v) mood stabilizers; vi) zinc; and vii) premenstrual drugs.

The compounds of the invention can be used in combination with the following agents to treat or prevent autism: i) antipsychotics; ii) antidepressants; iii) anxiolytics; and iv) stimulators, for example, methylphenidate, amphetamine and pemoline formulations.

The compounds of the invention can be used in combination with the following agents to treat or prevent ADHD: i) stimulants, for example, methylphenidate, amphetamine and pemoline formulations; and ii) non-stimulants, for example, norepinephrine reuptake inhibitors (such as atomoxetine), a2 adrenergic receptor agonists (such as clonidine), antidepressants, modafinil and cholinesterase inhibitors (such as galantamine and donezepil ).

The compounds of the invention can be used in combination with the following drugs to treat personality disorders: i) antipsychotics; ii) antidepressants; iii) mood stabilizers; and iv) anxiolytics.

The compounds of the invention can be used in combination with the following agents to treat or prevent male sexual dysfunction: i) phosphodiesterase V inhibitors, for example, vardenafil and sildenafil; ii) dopamine agonists / dopamine transport inhibitors, for example, apomorphine and bupropion; iii) adrenergic receptor antagonists to, for example, phentolamine; iv) prostaglandin agonists, for example, alprostadil; v) testosterone agonists, such as testosterone; vi) serotonin transport inhibitors, for example, serotonin reuptake inhibitors; v) noradrenaline transport inhibitors, for example, reboxetine; and vii) 5-HT1A agonists, for example, flibanserin.

The compounds of the invention can be used in combination with the same agents specified for male sexual dysfunction to treat or prevent female sexual dysfunction and, in addition, an estrogen agonist, such as estradiol.

Antipsychotics include typical antipsychotics (for example, chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixin, haloperidol, molindone and loxapine); and atypical antipsychotics (eg clozapine, olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone and amisulpride).

Antidepressants include serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, paroxetine and sertraline); dual serotonin / noradrenaline reuptake inhibitors (such as venlafaxine, duloxetine and milnacipran); norepinephrine reuptake inhibitors (such as reboxetine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide, phenelzine and tranylcypromine); and others (such as bupropion, mianserin, mirtazapine, nefazodone and trazodone).

Mood stabilizing drugs include lithium, sodium valproate / valproic acid / semisodium valproate, carbamazepine, lamotrigine, gabapentin, topiramate and thiagabine.

Anxiolytics include benzodiazepines, such as alprazolam and lorazepam.

It will be appreciated that the references herein to "treatment" extend to prophylaxis, prevention of recurrence and suppression or improvement of symptoms (both without being mild, if they are moderate or intense), as well as the treatment of established conditions.

The compound of the invention can be administered as the crude chemical, but the active ingredient is preferably present as a pharmaceutical formulation.

According to one more aspect, the invention discloses a pharmaceutical composition comprising a compound of the invention, in association with one or more pharmaceutically acceptable carriers, diluents and / or excipients. The vehicle, diluent and / or excipient must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not being detrimental to the recipient thereof.

The compounds of the invention can be administered in conventional pharmaceutical forms prepared by the combination of a compound of the invention with standard pharmaceutical vehicles or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as is most appropriate to obtain the desired preparation.

The pharmaceutical compositions of the invention can be formulated for administration by any route and includes those that are in a form adapted for oral, topical or parenteral administration to mammals, including humans.

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The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as sterile oral or parenteral solutions or suspensions.

The topical formulations of the present invention may be presented as, for example, ointments, creams or lotions, eye ointments and eye drops, impregnated bandages and aerosols, and may contain suitable conventional additives, such as preservatives, solvents to help the penetration of the drug and emollients into ointments and creams.

The formulations may also contain compatible conventional vehicles, such as cream or ointment bases and ethanol or oleic alcohol for lotions. Such vehicles may be present as from about 1% to about 98% of the formulation. More normally, they will form up to 80% of the formulation.

Tablets and capsules for oral administration may be in the form of a unit dose presentation and may contain conventional excipients, such as binders, for example, syrup, gum arabic, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; fillers, for example, lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; lubricants for the formation of tablets, for example, magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example, potato starch; or acceptable humectants such as sodium lauryl sulfate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Liquid oral preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or they may be present as a dry product for reconstitution with water or other suitable vehicle before being used. Such liquid preparations may contain conventional additives, such as suspending agents, for example, sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats, emulsifiers, for example, lecithin, monooleate sorbitan or gum arabic; non-aqueous vehicles (which may include edible oils), for example, almond oil, oily esters, such as glycerin, propylene glycol or ethyl alcohol; preservatives, for example, methyl or propyl p-hydroxybenzoate, or sorbic acid and, if desired, conventional flavoring or coloring.

Suppositories will contain bases of conventional suppositories, e.g. eg, cocoa butter or other glyceride.

For parenteral administration, liquid unit dosage forms are prepared with the compound and a sterile vehicle, with water being preferred. The compound, according to the vehicle and the concentration used, can be suspended or dissolved in the vehicle. When preparing the solutions, the compound can be dissolved in water for injection and sterilized in a filter before filling a suitable vial or vial and sealing it.

Advantageously, agents, such as local anesthetics, preservatives and buffers, can be dissolved in the vehicle. To improve stability, the composition can be frozen after filling the vial and removing the water in vacuo. Next, the dried lyophilized powder is sealed in the vial and a vial of accompanying water for injection can be supplied to reconstitute the liquid before being used. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of dissolving it, and sterilization cannot be performed by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending it in the sterile vehicle. Advantageously, a surfactant or humectant is included in the composition to facilitate uniform distribution of the compound.

The compositions may contain from 0.1% by weight, for example from 10% to 60% by weight, of the active material, depending on the method of administration. When the compositions comprise unit doses, each unit will contain, for example, 5 to 1000 mg of the active ingredient. The dose used for the treatment in adult humans can range from 10 to 3000 mg per day depending on the route and frequency of administration. For oral administration, a typical dose may be in the range of 50 to 1500 mg per day, for example, 120 to 1000 mg per day.

The person skilled in the art will recognize that the optimal amount and spacing of the individual doses of a compound of the invention will be determined by the nature and extent of the condition to be treated, the form, the route and the site of administration and the management concrete that is being treated, and that such optimal quantities can be determined by conventional techniques. The person skilled in the art will also appreciate that the optimal course of treatment, namely the number of doses of a given compound per day for a defined number of days, can be determined by the person skilled in the art through the conventional course of testing. of treatment determination.

It will be appreciated that the invention also includes the following aspects. The embodiments described for the first aspect apply equally to these other aspects. The diseases and conditions described above extend, when appropriate, to these other aspects:

i) A compound of the invention to be used for the treatment or prevention of a disease or condition mediated by the modulation of voltage-dependent sodium ionotrope channels.

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ii) Use of a compound of the invention for the manufacture of a medicament for treating or preventing a disease or condition mediated by the modulation of voltage dependent sodium ionotrope channels.

Examples

The invention is illustrated by the examples described below.

In the procedures that follow, after each starting material, the reference to a description or example is typically disclosed by a number. This is simply provided for expert chemist assistance. The starting material may not necessarily have been prepared from the lot to which reference is made.

When reference is made to the use of a "like" procedure, as those skilled in the art will appreciate, such a procedure could involve a minor variation, for example, reaction temperature, amount of the reactant or solvent, reaction time, reaction conditions, development or conditions of chromatographic purification.

The absolute configuration of the asymmetric centers within the spirited compounds prepared from achiral starting materials and resolved through the use of chiral chromatography have been assigned by a combination of optical rotation and NMR spectroscopy (to determine the relative stereochemistry of adjacent asymmetry centers) and these have been related to chiral intermediates and final compounds that have had their absolute configurations determined by X-ray crystallography on a single crystal.

Compounds are named with the ACD / Name PRO 6.02 chemical compound naming software program (Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada), or through the Lexichem automatic chemical compound naming software program (OpenEye Scientific Software Inc Santa Fe, New Mexico, USA).

Proton magnetic resonance (NMR) spectra are typically recorded on a Bruker instrument at 300, 400 or 500 MHz. Chemical shifts are given in ppm (6) using the residual solvent line as an internal reference. Division patterns are designated as s, singlet; d, double up; t, triplet; q, quadruplet; m, multiplet; br, width. NMR spectra were recorded at a temperature ranging from 25 to 90 ° C. When more than one conformer is detected, chemical shifts are described for the most abundant.

Liquid chromatography data coupled to mass spectrometry (LC-MS) is typically generated in a Waters ZQ mass spectrometer, which operates in alternating ES + and eS- ionization modes coupled to an Agilent 1100 Series HPLC system in line with Agilent 1100 UV-DAD and Sedere SEDEX 75 ELSD detection. Instrument control and data acquisition are carried out through the Waters MassLynx - OpenLynx software suite. The separation was performed on a Waters SunFire C18 column (30 x 4.6 mm, 3.5 pm). Flow rate: 3.0 ml / min. Column temperature: 30 ° C. Injection volume: 5.0 pl. Mobile phase [A]: 3: 97: 0.05 (v / v / v) acetonitrile: water: formic acid. Mobile phase [B]: 97: 3: 0.05 (v / v / v) acetonitrile: water: formic acid. Gradient: 97% [A] 3% [B] for 0.1 min. 3% ramp [A] 97% [B] at 4.0 min. Maintain 97% [B] for 5 min. Return to 97% [A] at 6 min. Detector parameters: UV-DAD: Range 190 to 450 nm, Range 2 nm, Threshold 0.1 mAU. ELSD: Temperature 40 ° C, Margin 8. Mass spectrometer: ES +: Mass margin: from 125 to 625 in 0.50 s. Delay between scans: 0.25 s. 4.0 kV capillary. ES-: Mass margin: from 125 to 625 in 0.50 s. Delay between scans: 0.25 s. 3.0 kV capillary.

In mass spectra, only one peak in the molecular ion cluster is usually described.

For reactions involving microwave irradiation, a Biotage Initiator was used.

Chiral chromatography was typically performed with a ChiralPak ™ AD-H or ChirakPak IA column from Daicel® with the use of heptane / ethanol or heptane / ethanol / methanol mixtures as eluent. Analytical chiral HPLC was performed in an Agilent 1100 series HPLC system, or in a Gilson HPLC system with a 250 x 4.6 mm column and a flow rate of 1 ml / min. Preparative chiral HPLC was performed with a Gilson preparative HPLC system or a 250 x 19 mm semi-preparative column at a flow rate of 18 ml / min.

Rapid silica gel chromatography was performed on a 230-400 mesh of silica gel (provided by Merck AG Darmstadt, Germany) or on prepackaged cartridges of Biotage silica or NH silica.

The optical rotations were measured with an automatic polarfometer Optical Activity Ltd AA-10 (Cambridge, GB) by a cell with a passage length of 10 cm and in a chloroform solution unless otherwise indicated.

SCX cartridges are solid phase extraction columns by ion exchange, supplied by Varian. The eluent used with SCX cartridges is methanol followed by a solution of 0.2 to 2.0 M ammonium in methanol.

In most preparations, purification was performed with the Biotage automatic rapid chromatography systems (SP4 or Isolera).

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The following abbreviations are used herein:

 Boc

 ferf-butyloxycarbonyl

 CBz

 benzyloxycarbonyl

 DCE

 1,2-dichloroethane

 DCM

 dichloromethane

 EtOAc

 ethyl acetate

 Et2O

 ether

 HCl

 rich chlorhfd acid

 HPLC

 High performance liquid chromatography

 K2CO3

 Potassium carbonate

 LC-MS

 Liquid chromatography coupled to mass spectrometry

 mCPBA

 metachloroperbenzoic acid

 MeCN

 acetonitrile

 MeOH

 methanol

 MgSO4

 magnesium sulphate

 Na2CO3

 sodium carbonate

 PdCl2 (Ph3P) 2

 bis (triphenylphosphine) palladium (II) chloride

 THF

 tetrahydrofuran

Description 1: 3 - [(£) - (4-Bromo-2-pyridyl) methyleneamino] -1-methyl-pyrrolidfn-2-one (D1)

To a stirred solution of 4-bromopyridine-2-carbaldehyde (2,232.1 mg, 12 mmol) in anhydrous DCM (60 ml) in nitrogen at room temperature was added 3-amino-1-methylpyrrolidfn-2-one racemic (1,506 , 8 mg, 13.2 mmol) [CAS: 2483-65-0] and magnesium sulfate (4,500 mg, 37.4 mmol). The resulting mixture was allowed to stir at room temperature overnight. It was filtered, and the filtrate was washed with semi-saturated saline solution. The organic layer was dried (Na2SO4) and evaporated to give 3 - [(£) - (4-bromo-2-pyridyl) methylenamino] -1-methylpyrrolidfn-2-one (D1) (3.15 g, 11 , 2 mmol, 93% yield), as a solid cream.

300 MHz 1H NMR 6h (CDCla) 2.30-2.41 (1H, m), 2.41-2.55 (1H, m), 2.94 (3H, s), 2.46 (1H, dt ), 3.60 (1H, ddd), 4.20 (1H, t), 7.50 (1H, d), 7.21 (1H, s), 8.48 (1H, s), 8.49 (1H, d).

Description 2: 3- (Benzenesulfonyl) -2- (4-bromo-2-pyridyl) -7-methyl-1,7-diazaspiro [4.4] nonan-6-one (D2)

A mixture of 3 - [(£) - (4-bromo-2-pyridyl) methylemino] -1-methyl-pyrrolidfn-2-one (which can be prepared as described in description 1) (564.3 mg, 2 mmol) and phenylvinylsulfone (339.8 mg, 2.02 mmol) in THF (10 ml) was treated with silver acetate (333.99 mg, 2 mmol). The mixture was stirred at room temperature for 2 hours, filtered through Celite and concentrated to give the title compound (D2) as a brown gum;

M / Z: 450, 452 (M + H +)

Description 3: (5R) -2- (4-Bromo-pyridfn-2-yl) -7-methyl-1,7-diazaspiro [4.4] non-1-en-6-one (D3R) and (5S) - 2- (4-Bromo-pyridfn-2-yl) -7-methyl-1,7-diazaspiro [4.4] non-1-en-6-one (D3S)

METHOD A

A mixture of 3- (benzenesulfonyl) -2- (4-bromo-2-pyridyl) -7-methyl-1,7-diazaspiro [4.4] nonan-6-one (which can be prepared as described in description 2) (900.7 mg, 2 mmol) in THF (10 ml) in nitrogen at 0 ° C was treated with potassium ferf-butoxide in THF (2.94 ml, 5 mmol) in portions for 10 minutes. The mixture was stirred at 0 ° C for 1 hour and then acetic acid (0.29 ml, 5 mmol) was added, and the mixture was filtered through Celite and then concentrated. Chromatography of the crude material on a Si-NH column (0 to 80% ethyl acetate in isohexane) gave 329 mg of the racemic mixture of the title compounds as a cream solid.

300 MHz 1H NMR 6h (CDCla) 1.89-1.96 (1H, m), 2.13-2.23 (1H, m), 2.44 (1H, ddd), 2.58 (1H, ddd ), 2.97 (3H, s), 3.203.44 (3H, m), 3.66-3.74 (1H, m), 7.70 (1H, d), 8.85 (1H, s) , 8.97 (1H, d).

5

10

fifteen

twenty

25

30

35

40

Four. Five

fifty

This was separated into two enantiomers by chiral chromatography with a ChiralPak AD-H column eluted with 15% ethanol in heptanes. The optical rotation of the isomers is based on the analysis of purified samples separately;

Rapid isomer: (R) -2- (4-Bromo-pyridfn-2-yl) -7-methyl-1,7-diazaspiro [4.4] non-1-en-6-one (D3R);

Optical rotation at [D / 22] = +86.9 (c = 1, CHCh).

Slow isomer: (S) -2- (4-Bromo-pyridfn-2-yl) -7-methyl-1,7-diazaspiro [4.4] non-1-en-6-one (D3S);

Optical rotation a [D / 22] = +85.8 (c = 1, CHCh).

Method B

To a stirred solution of 3 - [(£) - (4-bromo-2-pyridyl) methylemino] -1-methyl-pyrrolidfn-2-one (which can be prepared as described in description 1) (8 , 1 g, 28,709 mmol) in anhydrous THF (80 ml) in nitrogen at room temperature, phenylvinylsulfone (4,926 g, 29,283 mmol) and silver acetate (0.53 g, 3.18 mmol) were added. The resulting mixture was allowed to stir at room temperature for 1.5 hours. The reaction mixture was filtered through Celite and the filtrate was stirred in nitrogen in an ice bath and treated with potassium t-butoxide (33.78 ml of 1.7 M solution in THF, 57.42 mmol) for 5 minutes. After completing the addition, the mixture was stirred at room temperature for 1 hour, acetic acid (3.29 ml, 57.42 mmol) was added and the mixture was stirred for 5 minutes and then filtered through Celite and He concentrated. Chromatography (Biotage Si-NH column, 10 to 100% ethyl acetate in isohexane) followed by trituration of the isolated product with ether and vacuum drying gave the title compounds as 5.74 g of an off-white solid ( racemic). Purification as in method A gave the enantiomers separately.

Description 4: (2R, 5S) -2- (4-Bromo-2-pyridyl) -7-methyl-1,7-diazaspiro [4.4] nonan-6-one (D4R) and (2S, 5S) -2- (4- Bromo-2-pyridyl) -7-methyl-1,7-diazaspiro [4.4] nonan-6-one (D4S)

To a stirred solution of (5S) -2- (4-bromo-pyridfn-2-yl) -7-methyl-1,7-diazaspiro [4.4] non-1-en-6-one (which can be prepared such and as described in description 3) (1.08 g, 3.5 mmol) in anhydrous DCM (18 ml) in nitrogen at room temperature, concentrated HCl (0.37 ml, 3.68 mmol) was added and, after 5 minutes, sodium triacetoxyborohydride (2,226.21 mg, 10.5 mmol). The resulting mixture was allowed to stir at room temperature for 1 hour. The saturated Na2CO3 solution (approximately 3 ml) was added and the mixture was stirred for 10 minutes. The solvents were evaporated and DCM was added, and the solution was dried with Na2SO4, filtered and evaporated to give a yellow oil (approximately 1.1 g) which was purified by flash chromatography on silica KP-NH (ethyl acetate). 0 to 100% in isohexane) to give 614 mg of the predominant trans isomer (D4R) and 379 mg of an approximately 6: 1 mixture of the cis isomer (D4S) and the trans isomer. The trans isomer was further purified by preparative chiral HPLC. Characterization based on separately purified isomers gave the trans isomer (2R, 5S) -2- (4-bromo-2-pyridyl) -7-methyl-1,7-diazaspiro [4.4] nonan-6-one (D4R) ;

300 MHz 1H NMR 6h (CDCla) 1.82-1.95 (2H, m), 2.00-2.24 (3H, m), 2.5 (1H, br s), 2.47-2, 59 (1H, m), 2.90 (3H, s), 3.26-3.37 (2H, m), 4.68 (1H, t), 7.32 (1H, d), 7.75 (1H, s), 8.34 (1H, d).

Isomer cis (2S, 5S) -2- (4-bromo-2-pyridyl) -7-methyl-1,7-diazaspiro [4.4] nonan-6-one (D4S);

300 MHz 1H NMR 6h (CDCla) 1.76-1.87 (1H, m), 1.99-2.20 (4H, m), 2.29-2.40 (1H, m), 2.8 (1H, br s), 2.90 (3H, s), 2.28-3.41 (2H, m), 4.38 (1H, t), 7.33 (1H, d), 7.75 (1H, s), 8.38 (1H, d).

Description 5: 3- (Benzhydrylideneamino) -1-methyl-pyrrolidfn-2-one (D5)

The benzophenone imine (200.04 g, 1,103.8 mmol) was added dropwise over 20 minutes to a stirred solution of 2-aminopyrrolidinone (120 g, 1.051.2 mmol) in DCE (1000 ml) at room temperature in nitrogen in a 2 l flask adapted with a magnetic stir bar. The reagent was washed further with DCE (100 ml). The stirred solution was heated with reflux in a thermal block at a temperature of the block of 95 ° C for 7 h, using a N2 bubbler that exhaled the gas that had passed through a safety trap and then inside 2 l of water through a funnel face up (to discard NH3 gas, which is estimated to be approximately 23 l). The reaction is allowed to stand at room temperature overnight in N2. The mixture was evaporated to give a thick whitish oil. To this was added Et2O (700 ml) and to this stirred solution, as soon as it began to crystallize, isohexane (700 ml) was added for 2 minutes. Then, the mixture was stirred for 1 h and then filtered with suction and washed with Et2O / isohexane (1: 1) (500 ml). The white solid was dried at 35 ° C under vacuum for 3 h to provide 3- (benzhydrylideneamino) -1-methyl-pyrrolidfn-2-one (D5) (259.4 g, 88.6%);

300 MHz NMR 6h (CDCfa) 2.15-2.49 (2H, m), 2.90 (3H, s), 3.26-3.34 (1H, abq), 3.52 (1H, dt) , 4.23 (1H, t), 7.30-7.49 (8H, m), 7.63-7.67 (2H, m).

Description 6: 3- (Benzhydrylideneamino) -1-methyl-3-prop-2-inyl-pyrrolidfn-2-one (D6)

The potassium ferf-butoxide at 1.7 M in THF (602.08 ml, 1023.5 mmol) was added dropwise over a period of 2.5 h to a stirred solution of 3- (benzhydrylideneamino) -1-methyl -pyrrolidm-2-one (259 g, 930.48 mmol) (which can be prepared as described in description 5) and an 80% solution of propargyl bromide in 5 toluene (124.37 ml, 1116 , 6 mmol) in THF of dry reagent grade in a 3A molecular sieve (1,900 ml) at -65 ° C in nitrogen, in a 5 l flask equipped with a stirrer at the top. After the addition was complete, the mixture was stirred at -65 ° C for an additional 1 h. The cooling bath was removed and a saturated NaHCO3 solution (140 ml) was added for 1 minute (at -60 ° C). After 5 more minutes, the saturated NaHCO3 solution (1.4 L) was added followed by Et2O (1.4 L). The mixture was stirred for 1 h, then transferred to a separatory funnel and water (1.4 L) was added to dissolve all solids. The layers were separated and the aqueous layer was further extracted with Et2O (2 x 1 L). The combined organic extracts were washed again with saturated saline solution (700 ml), and diluted with water (700 ml). The organic layer was dried (MgSO4) and evaporated in a volume of approximately 500-600 ml after which crystallization began to occur. Then, to this stirred mixture was added isohexane (1.6 L). After standing for 15 min, the cream solid was filtered by suction, washed with isohexane (500 ml), and dried at 50 ° C under vacuum for 5 h. This gave 3- (benzhydrylideneamino) -1-methyl-3-prop-2-inyl-pyrrolidm-2-one (D6) (274 g, 93%). This was pure by NMR, but it contained some additional water;

300 MHz NMR 6h (CDCla) 1.95 (1H, t), 2.14-2.24 (1H, m), 2.44 (3H, s), 2.45-2.64 (2H, m) , 2.94 (2H, t), 3.11 (1H, dt), 7.23-7.48 (8H, m), 7.55-7.59 (2H, m).

Description 7: (3S) -3-Amino-1-methyl-3-prop-2-inyl-pyrrolidfn-2-one (D7S) and (3R) -3-amino-1-methyl-3-prop-2 -inyl- pyrrolidfn-2-one (D7R)

Method A: To a stirred solution of 3- (benzhydrylideneamino) -1-methyl-3-prop-2-inyl-pyrrolidm-2-one (274 g, 865.99 mmol) (which can be prepared as described in description 6) in a 5 l flask equipped with a stirrer at the top, in THF (2.7 l), citric acid monohydrate (363.96 g, 1,732 mmol) was added in one portion. The solution was stirred at room temperature for 18 h, to give a thick white precipitate with some sticky solid adhered to the flask walls. This sticky solid was released with a spatula, then diethyl ether (1.3 L) was added and continued with rapid agitation for 1 h more. Then, the solid was filtered by suction, washed effectively with Et2O (2 x 1 L) and dried at 50 ° C under vacuum for 3 hours. This produced 268 g of material. This was retrocrystallized from hot MeOH (1.9 L); The hot solution was filtered by suction to give a transparent pale yellow solution. The solution was allowed to stand for 1 h and Et2O (3 L) was added with stirring. After standing for 1 h more, the mixture was filtered and washed with MeOH: Et2O (1: 2) (1 L), the solid was pressed to dry and dried more at 50 ° C under vacuum for 6 hours to provide 312 g of the citrate salt, contaminated with methanol. In a separate container, the Ambersep 900 (OH) ion exchange resin (2.31 kg, 2,722.7 mmol) was stirred for 5 minutes with MeOH (2 L) for pre-washing of the resin. The suspended resin 35 was filtered by suction and the previously washed wet resin was still added to a stirred suspension of the citrate salt previously prepared in methanol (3 L) in a 10 L vessel equipped with a stirrer at the top. The mixture was stirred for a total of 1.5 h at room temperature and then filtered by suction. The filtered resin was washed with MeOH (2 x 1.5 L). The filtrate and washings were evaporated in vacuo to give an oil that was re-dissolved in DCM (1.5 L) and dried (Na2SO4), filtered and evaporated in a pale yellow oil, which was dried at 40 RT. overnight to give 3-amino-1-methyl-3-prop-2-inyl-pyrrolidm-2-one (D7) (106.9 g, 79.9%);

300 MHz NMR 6h (CDCla) 1.65 (3H, br.s), 1.94-2.05 (2H, m), 2.31-2.39 (1H, m), 2.41-2, 55 (2H, m), 2.89 (3H, Me), 3.33-3.39 (2H, m).

A portion of this material (1.75 g, 11.5 mmol) was separated by chiral HPLC using an AD-H semiprep column, elution with 20% EtOH / heptane at 18 ml / min. The peaks at 215 nm were identified:

45 (3S) -3-amino-1-methyl-3-prop-2-inyl-pyrrolidm-2-one (D7S) 549 mg, retention time = 13.7 min (37.5%); Rotation

optics at [D / 22] = -81.0 (c = 0.975, CHCh);

(3R) -3-amino-1-methyl-3-prop-2-inyl-pyrrolidm-2-one (D7R) 407 mg, retention time = 17.9 min (36.4%); Optical rotation a [D / 22] = +78.8 (c = 0.965, CHCh).

Method B: (3S) -3-Amino-1-methyl-3-prop-2-inyl-pyrrolidfn-2-one (D7S)

50 A controlled laboratory reactor with a heated / cooled jacket and a vane shaker on the top was charged with IPA (2,250 ml) and acid (2S) -2- (6-methoxy-2-naphthyl) was added. propanoic acid (84.72 g, 367.92 mmol). The suspension was stirred and heated to 75 ° C, which gave a solution. Next, a solution of 3- amino-1-methyl-3-prop-2-inyl-pyrrolidm-2-one (which can be prepared as described in description 7, method A) was added (55, 99 g, 367.92 mmol) in IPA (1100 ml) dropwise over 1.5 hours. The reaction mixture was stirred at 75-75 ° C for 1 h, and then cooled to 55 ° C for 1 h. The reaction was fed with the salt of the isomer (S)

pure in each coffee of 1 degree of temperature until the inoculum remained out of the solution (approximately 71 ° C). The reaction mixture was crystallized and stirred at 55 ° C for 1 h. The mixture was then cooled to 40 ° C for approximately 20 minutes and filtered by suction in a preheated filter funnel.

on a quick filter paper. The vessel was rinsed with IPA (600 ml) preheated to 40 ° C and this was used to wash the collected solids. The solids were dried by suction until there was no more solvent and then dried in a vacuum oven at 50 ° C to give a white solid, 59.37 g, of (2S) -2- (6-methoxy-2- (3S) -1-Methyl-2-oxo-3-prop-2-inyl-pyrrolidfn-3-yl] ammonium naphthyl) propanoate. A portion of this material was removed and dissolved in methanol, passed through an SCX column, washed with methanol and then eluted with 0.5 M ammonium in methanol. The ammonium eluate was evaporated to give a pale yellow gum, which was analyzed by chiral HPLC (20:80 EtOH: heptane, column IA) and showed the 99.5% S isomer and the 0.5% R isomer. The Ambersep 900-OH (500 g, 155.24 mmol) was stirred in methanol (1000 ml) for 5 minutes, then filtered and dried by suction until no more liquid appeared. The washed resin was added to a stirred suspension of the salt of the S-isomer (59.37 g, 155.24 mmol) in methanol (1000 ml). The mixture was stirred for 1 h and then filtered. The resin was resuspended in methanol (1,000 ml), stirred for one hour and then filtered. The combined filtrates were evaporated to give a slightly cloudy yellow oil. The oil was dissolved in dichloromethane (approximately 200 ml) and dried over magnesium sulfate, filtered and evaporated to give a transparent yellow oil of (3S) -3-amino-1-methyl-3-prop-2-inyl -pyrrolidfn-2-one (D7S) (22,729 g). This material was identical from the spectroscopic point of view to that prepared with chiral chromatography in method A.

Method C: (3R) -3-Amino-1-methyl-3-prop-2-inyl-pyrrolidfn-2-one (D7R)

The enriched mother liquors for backcrystallization containing, for example, a 91: 9 ratio of the naproxen salt of (3R) -3-amino-1-methyl-3-prop-2-inyl-pyrrolidfn-2-one and its enantiomer (3S) (27 g) (which can be obtained from the fractional crystallization process described in method B) was evaporated and dissolved in acetonitrile at 30 ° C ± 5 ° C. The reaction mass was heated to 70 ° C ± 5 ° C, stirred for 10 minutes, and then slowly cooled to 40 ° C ± 2 ° C. An inoculum of the R-amine-naproxen salt was introduced and the reaction mixture was maintained at 40 ° C ± 2 ° C for 1 hour. The reaction mass was cooled to 30 ° C ± 5 ° C and filtered. The isolated salt was washed with acetonitrile and dried in vacuo at 47.5 ° C ± 2.5 ° C for 6 ± 1 hours to give 18.2 g of the salt with a 99.8% enantiomeric excess of the R isomer Next, the material was converted to the free base form 25 as described for the S enantiomer in method B to give the title compound (D7R). This material was identical from the spectroscopic point of view to that prepared by chiral chromatography in method A.

Description 8: W - [(3S) -1-Methyl-2-oxo-3-prop-2-inyl-pyrrolidfn-3-yl] fert-butyl carbamate (D8)

To a solution of (3S) -3-amino-1-methyl-3-prop-2-inyl-pyrrolidfn-2-one (which can be prepared as described in description 7) (72.66 g, 477.4 mmol) in DCM (1,000 ml) was added a solution of Boc2O (125.03 g, 572.88 30 mmol) in DCM (700 ml) in one portion. Then, the reaction was stirred at 40 ° C (bath temperature, not internal temperature) for 5 h, and then at room temperature for a weekend. The reaction was concentrated in vacuo, and the residue was suspended in a mixture of Et2O and isohexane (1: 1, 250 ml) and stirred for 30 minutes. The suspension was filtered and the solid was washed with a mixture of Et2O and isohexane (1: 1, 250 ml), followed by isohexane (3 x 250 ml). Next, the solid was dried in a vacuum oven for 2 hours (40 ° C) to give a white solid of W - [(3S) -1-methyl-2-oxo-3-prop-2-inil- pyrrolidfn-3-yl] ferf-butyl carbamate (D8) (99.25 g);

300 MHz NMR 6h (CDCla) 1.43 (9H, s), 2.01 (1H, app.t), 2.45-2.59 (3H, m), 2.78, 2.82 (1H, 2 x br.s), 2.81 (3H, s), 3.35-3.45 (2H, m), 5.23 (1H, br.s).

A second crop of the filtrate was isolated to give another batch, 5.535 g of similar purity.

Description 9: 2-Iodine-4- [3- (trifluoromethoxy) phenyl] pyridine (D9)

40 Acetyl chloride (4.45 ml, 62.6 mmol) was added to a solution of 2-chloro-4- [3- (trifluoromethoxy) phenyl] -pyridine [CAS 1261856-64-7] (11.42 g , 41.73 mmol) and sodium iodide (31.28 g, 208.67 mmol) in MeCN (200 ml) in N2, and the resulting suspension was heated at 80 ° C for 18 h. More sodium iodide (20 mol%) was added and stirring was continued for 3 h. The reaction was cooled and the mixture was treated with aqueous sodium carbonate. After 5 minutes, the solid sodium metabisulfite was added until the discoloration was achieved. Water was added to re-dissolve a precipitate that had formed. The mixture was diluted with EtOAc and the layers were separated. The aqueous layer was washed with EtOAc (2x), the combined organic layers were dried (MgSO4) and the solvent was evaporated to provide crude 2-iodine-4- [3- (trifluoromethoxy) phenyl] pyridine (D9) (16, 3 g) as an amber oil containing approximately -5% of the reduced 2-H material and -8% of the starting material of the unreacted chloride.

50 300 MHz 6h NMR (CDCla) 7.35 (1H, t) 7.42-7.28 (2H, m), 7.52-7.58 (2H, m), 7.95 (1H, s) , 8.46 (1H, d).

Description 10: W - [(3S) -1-Methyl-2-oxo-3- [3- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] prop-2-inyl] pyrrolidfn-3-

il] fert-butyl carbamate (D10)

Copper iodide (104.92 mg, 0.5500 mmol), followed by PdC ^ PhbP ^ (193.34 mg, 0.2800 mmol) were added portionwise to a solution of W - [(3S) -1- methyl ferro-butyl methyl-2-oxo-3-prop-2-inyl-pyrrolidfn-3-yl] carbamate (2.78 g, 11.02 55 mmol) (which can be prepared as described in the description 8), 2-iodo-4- [3- (trifluoromethoxy) -phenyl] pyridine (6.03 g, 16.53 mmol) (which can be prepared as described in description 9) and Et2NH (5, 7 ml, 55.09 mmol) in THF (60 ml) in N2 and the reaction was stirred at 20 ° C for 18 hours. More catalyst was added

PdCl2 (Ph3P) 2 (1.25 mol%) and CuI (2.5 mol%). The reaction was left under stirring for 3 days. The solvent was evaporated and the residue suspended in EtOAc and washed with water / saturated aqueous NaHCO3. The organic layers were collected, dried (Na2SO4) and the solvent evaporated to provide a brown oil. This was purified by a Biotage SP4, with a 100g SNAP cartridge, and eluted with 0 to 100% EtOAc in i-hexane. Clean fractions were collected and the solvent was evaporated to provide a yellow oil. The remaining fractions were collected and re-passed through a column with a 100g SPAP SNAP cartridge, 0 to 10% MeOH / EtOAc and the product was collected and combined with the clean material of the first column to provide the N- [(3S) -1-methyl-2-oxo-3- [3- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] prop-2-inyl] pyrrolidfn-3-yl] ferf- carbamate butyl (D10) (5.38 g, 10.991 mmol, 99.8% yield) as a yellow oil containing some Ph3P residues;

10 300 MHz NMR 6h (CDCh) 1.45 (9H, s), 2-49-2.72 (2H, m), 2.82 (1H, d), 2.95 (3H, s), 3, 11 (1H, d), 3.42 (1H, t), 3.57

(1H, q), 5.31 (1H, br.s), 7.34 (1H, d), 7.43 (1H, d), 7.48 (1H, s), 7.54-7, 61 (3H, m), 8.64 (1H, d).

Description 11: (3S) -3-Amino-1-methyl-3- [3- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] prop-2-inyl] pyrrolidfn-2-one

(D11)

Method A: Trifluoroacetic acid (10 ml, 134.63 mmol) was added to a solution of N - [(3S) -1-methyl-2-oxo-3- [3- [4- [3- 15 (trifluoromethoxy)) phenyl] -2-pyridyl] prop-2-inyl] pyrrolidfn-3-yl] ferf-butyl carbamate (which can be prepared as described in description 10) (5.38 g, 10.99 mmol) in DCM (50 ml) at 20 ° C and the reaction was stirred until complete. Solid K2CO3 was added to deactivate the present TFA and the mixture was diluted with water. The phases were separated and the aqueous layer was washed with dichloromethane (x2). The combined organic layers were dried (MgSO4) and the solvent was evaporated to give the (3S) -3-amino-1-methyl-3- [3- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] prop-2-inyl] pyrrolidfn-2-20 one (D11) (4.78 g, 12.276 mmol, 111.7% yield) as an amber oil containing some Ph3PO;

300 MHz 1H NMR 6h (CDCh) 1.82 (2H, br.s), 2.08 (1H, dt), 2.48 (1H, ddd), 2.78 (2H, abq), 2.93 ( 3H, s), 3.38-3.47 (2H, m), 7.34 (1H, d), 7.43 (1H, dd), 7.47 (1H, s), 7.51-7 , 62 (3H, m), 8.66 (1H, d).

Method B: A solution of N - [(3S) -1-methyl-2-oxo-3- [3- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] prop-2-inyl] pyrrolidfn- 3- il] ferf-butyl carbamate (8.91 g, 18.19 mmol) (which can be prepared as described in description 10) 25 in 1,4-dioxane (70 ml) was cooled in a ice bath and treated dropwise with concentrated H2SO4 (7.4 ml, 93.22 mmol). The mixture was allowed to reach room temperature and, after 45 min, the mixture was again cooled in an ice bath and treated cautiously with a solution of saturated aqueous Na2CO3 (~ 150 ml). The mixture was diluted with ethyl acetate (200 ml) and the product was extracted into ethyl acetate (2 x 150 ml). The combined organic extracts were dried (Na2SO4) and concentrated to give the title compound (D11) as an orange oil (6.88 g, 97%) that coincided spectroscopically with that prepared by method A .

Description 12: (5S) -7-Methyl-2- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] -1,7-diazaspiro [4.4] non-1-en-6-one (D12)

Silver trifluoromethanesulfonate (564.86 mg, 2.2 mmol) was added to a solution of (3S) -3-amino-1-methyl-3- [3- [4- [3- (trifluoromethoxy) phenyl] -2 -pyridyl] prop-2-inyl] pyrrolidfn-2-one (which can be prepared as described in description 11) (4.28 g, 10.99 mmol) in MeCN (60 ml) at 40 ° C and the reaction was stirred for 18 hours. 35 plus AgOTf (10 mol%) was added and stirring was continued for 24 hours. The solvent was evaporated and the rest was suspended in EtOAc. The organic phase was washed with water, dried (Na2SO4) and the solvent evaporated to provide a light brown oil. This was purified with an Isolera, with a SNAP cartridge of (50 + 100) g, eluting it with 0 to 100% (1% mixture of NH3 at 2 M in MeOH; 9% MeOH; 90% EtOAc) in EtOAc, which provides (5S) -7-methyl-2- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] -1,7-diazaspiro [4.4] non-1-en-6-one (D12) (3.17 40 g, 8.1414 mmol, 74.1% yield) as a light brown solid;

300 MHz 1H NMR 6h (CDCh) 1.95 (1H, ddd), 2.19 (1H, dt), 2.46 (1H, ddd), 2.59 (1H, ddd), 2.97 (3H, s), 3.26-3.49 (3H, m), 6.68 (1H, dt), 7.32 (1H, d), 7.50-7.56 (3H, m), 7.64 (1H, d), 8.36 (1H, s), 8.74 (1H, d).

Description 13 and description 14: (2R, 5S) -7-Methyl-6-oxo-2- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] -1,7-

diazaspiro [4.4] nonano-1-carboxylic acid ferf-butyl (D13) and (2S, 5S) -7-methyl-6-oxo-2- [4- [3- (trifluoromethoxy) phenyl] - 45 2-pyridyl] -1,7-diazaspiro [4.4] nonano-1-ferf-butyl carboxylate (D14)

Concentrated aqueous hydrochloric acid (698.76 pl, 8.14 mmol) was added to a solution of (5S) -7-methyl-2- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] -1, 7-diazaspiro [4.4] non-1-en-6-one (which can be prepared as described in description 12) (3.17 g, 8.14 mmol) in DCM (60 ml) at 0 ° C. Finally, sodium triacetoxyborohydride (5.18 g, 24.42 mmol) was added in a single portion and the resulting mixture was stirred for 18 hours. The reaction was stopped by adding saturated aqueous Na2CO3 and stirring was continued for 5 min. The phases were separated, the organic layer was dried (Na2SO4) and the solvent was evaporated to provide an amber oil (3.24 g), a 2.3: 1 mixture of the 2S and 2R isomers of (5R) -7- methyl-6-oxo-2- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] -1,7-diazaspiro [4.4] nonane (3.18 g, 8.12 mmol). This was dissolved in DCE (60 ml) and Boc2O (2.4 g, 11.01 mmol) was added and the reaction was stirred at 40 ° C for 3 days. The solvent was evaporated to provide a brown oil. This was purified with a Biotage 55 SP4, with a 100g SNAP cartridge, and eluted with EtOAc followed by 0 to 10% MeOH in EtOAc. The first to elute, the isomer (2S, 5S) -7-methyl-6-oxo-2- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] -1,7-diazaspiro [4.4] nonano-1- ferf-butyl carboxylate (D14) (1.03 g, 2.0956 mmol, 25.8% yield), and it was found to contain rotamers in the NMR spectrum;

300 MHz 1H NMR 8h (CDCI3) 1.18 1.45 (9H, 2 xs), 1.72-1.82 (1H, m), 1.98-2.24 (3H, m), 2.35 -2.78 (2H, m), 2.94, 2.98 (3H, 2 xs), 3.25-3.55 (2H, m), 5.11, 5.20 (1H, 2 xd) , 7.22-7.31 (1H, m), 7.35-7.42 (1H, m), 7.50-7.61 (1H, m), 7.66-7.70 (1H, m), 7.79, 7.91 (1H, 2 xd), 8.59-8.63 (1H, m), 8.66, 8.87 (1H, 2 xs).

The slowest isomer, (2R, 5S) -7-methy-6-oxo-2- [4- [3- (trifluoroomethoxy) phenyl] -2-pyridi] -1,7-diazaspiro [4.4] nonano-1 - 5 terf-butyl carboxylate (D13) (2.85 g, 5.7896 mmoI, yield of 71.4%) also showed rotamers in the NMR spectrum;

300 MHz 1H NMR 5h (CDCI3) 1.18, 1.41 (9H, 2 xs), 1.95-2.29 (4H, m), 2.54-2.69 (1H, m), 2, 79-3.03 (1H, m), 2.91, 2.95 (3H xs), 3.29-3.60 (2H, m), 5.16, 5.32 (1H, 2 x dd) , 7.29-7.58 (6H, m), 8.62-8.67 (1H, m).

Description 15: (2S, 5S) -7-Methyl-6-oxo-2- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] -1,7-diazaspiro [4.4] nonano-1-

10 fert-butyl carboxylate (D15)

A solution of Ia (2S, 5S) -7-methy-2- [4- [3- (trifluoroomethoxy) feniI] -2-pyridi] -1,7-diazaspiro [4.4] nonan-6-one gross (which is it can isolate taI and as described in example 2, method B) (111 mg, 0.2800 mmoI) in DCM (3 ml) containing a portion of the isomer (2R) treated with Boc2O (0.08 g, 0 , 3700 mmoI) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by chromatography with a 10g SNAP cartridge of 10g of Biotage, and used with ethylacetate to give the compound of the liquid (D15) as a white solid (124.5 mg).

M / Z: 392 (M + H +) 492

Example 1: (2R, 5S) -7-methyl-2- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] -1,7-diazaspiro [4.4] nonan-6- one (E1) hydrochloride

twenty

At a solution of Ia (2R, 5S) -2- (4-bromo-2-pyridiI) -7-methy-1,7-diazaspiro [4.4] nonan-6-one (which can be prepared as and as described in description 4) (22 mg, 0.0709 mmoI) in MeCN (1 mI) and water (0.2000 mI) in a Smith microwave vessel, acidic [3- (trifluoroomethoxy) phenyl] boronic acid (14,605 mg) was added , 0.0709 mmoI), bis (triphenylphosphine) paIadium (II) dichloride (2,4891 mg, 0.0035 mmoI) and sodium carbonate (15,035 mg, 0.1418 mmoI). The reaction vessel was dried and purged with nitrogen. The reaction mixture was heated with microwave at 100 ° C for 25 minutes. The reaction mixture was treated with water and extracted with DCM twice, and the organic layers were collected by passing through a PhaseSep cartridge. It was added additionally in an SCX-2 cartridge (0.5 g) and washed with DCM followed by MeOH. The desired product was removed from the cartridge by means of ammonium in MeOH (0.2 M). Evaporation of the solvents gave a yellow oil. It was further purified by a preparative HPLC column (ChiraIPak AD-H), used with ethane / n-heptane (1: 3) to give the desired product as an amber oil;

300 MHz 1H NMR 5h (CDCI3) 1.86-2.28 (5H, m), 2.50-2.62 (1H, m), 2.8 (1H, br s), 2.91 (3H, s), 2.25-3.89 (2H, m), 4.77 (1H, t), 7.29 (1H, d), 7.32 (1H, d), 7.48 (1H, t ), 7.53 (1H, q), 7.60 (1H, d), 7.70 (1H, s), 8.62 (1H, d).

This was converted into (2R, 5S) -7-methy-2- [4- [3- (trifluoroomethoxy) feniI] -2-pyridiI] -1,7-diazaspiro [4.4] - 35 nonan-6- hydrochloride one (E1) by adding HCI (1 M in dietary ether) to a free base solution in DCM. Evaporation followed by additional drying under reduced pressure gave an amber solid. The latter was further dried under reduced pressure at 40 ° C to give the final compound with a yield of 58%;

M / Z: 392 (M + H +).

image10

5

10

fifteen

twenty

25

30

35

40

image11

Method A. (2R, 5S) -7-methyl-6-oxo-2- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] -1,7-diazaspiro [4.4] nonan-1-carboxylate of ferf-butyl (which can be prepared as described in description 13) (2.85 g, 5.8 mmol) was added to a solution of 4M HCl in dioxane (10 mL, 40 mmol) in DCM (20 ml) at 20 ° C and the reaction was stirred for 18 hours. The solvent was evaporated and the residue was suspended in DCM. This was treated with saturated aqueous NaHCO3 and the phases were separated. The aqueous layer was washed with DCM (3x), the combined organic layer was dried (Na2SO4) and the solvent was evaporated to provide an amber oil (2.32 g). This was purified on a 100g SNAP cartridge, with 0 to 10% MeOH in EtOAc. The desired clean product fractions were collected and the solvent was evaporated to provide the (2R, 5S) -7-methyl-2- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] -1,7-diazaspiro [4.4] nonan-6-one as a pale yellow oil identical to that prepared in example 1.

Sulfuric acid (0.26 ml, 4.6 mmol) was added to a solution of this material (1.8 g, 4.6 mmol) in DCM (17 ml) at 20 ° C and the reaction was stirred for 5 min . The solvent was evaporated and the residue was dissolved in deionized water. This was lyophilized for 20 hours to give the (2R, 5S) -7-methyl-2- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] -1,7-diazaspiro hemisulfate hydrate [4.4] nonan-6-one (E2) (2.14 g) as a colorless solid;

300 MHz 1H NMR 6h (MeOD) 2.26-2.49 (4H, m), 2.70 (1H, dt), 2.82-2.91 (1H, m), 2.98 (3H, s ), 3.56 (2H, dd), 5.31 (1H, m), 7.46 (1H, d), 7.68 (1H, t), 7.82 (1H, s), 7.77 (1H, dd), 7.83 (1H, d), 7.87 (1H, s), 8.73 (1H, d).

Method B. A solution of the (5S) -7-methyl-2- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] -1,7-diazaspiro [4.4] non-1-en-6- One (which can be prepared as described in description 12) (5.77g, 14.82 mmol) in DCM (75 ml) was cooled to -78 ° C in nitrogen and a solution was added dropwise of the borane ferf-butylamine complex (1.43 g, 16.44 mmol) in DCM (15 ml), and keeping the internal temperature below -70 ° C for 10 min. The mixture was stirred at -78 ° C for 90 min and then the cooling bath was removed and 5M hydrochloric acid (30 ml, 150 mmol) was added through a dropping funnel for 1 to 2 min. The mixture was brought to 25-30 ° C with a Marfa bath and the mixture was stirred vigorously for 30 min. More DCM (200 ml) was added and then the mixture was slowly poured into a beaker containing sodium carbonate (17.28 g, 163.01 mmol) in water (150 ml) and the mixture was stirred for 10 min . The layers were separated and the aqueous layer (pH 9) was reextracted with DCM (2 x 150 ml). The combined organic layers were washed with saline, dried (Na2SO4) and concentrated to give a yellow gum, a 15: 1 mixture of the isomers (2R, 5S) and (2S, 5S). This mixture was separated by chromatography with a 340g SNAP cartridge from Biotage and elution with 5% 0.5M methanol ammonium in isocratic ethyl acetate to obtain the main isomer (2R, 5S) -7-methyl-2 - [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] -1,7-diazaspiro [4.4] nonan-6-one (5.76 g), increasing to 10% methanol ammonium to 0.5 M to elute the minor isomer (2S, 5S) -7-methyl-2- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] -1,7-diazaspiro [4.4] nonan-6-one (111 mg ) that was contaminated with traces of the isomer (2R, 5S). The isomer (2R, 5S) was identical from the spectroscopic point of view to the one prepared in Example 1. Next, it became the salt form: Sulfuric acid (0.75 ml, 13.48 mmol) was added at solution of (2R, 5S) -7-methyl-2- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] -1,7- diazaspiro [4.4] nonan-6-one (5.27 g , 13.48 mmol) in DCM (70 ml) at 20 ° C and the reaction was stirred for 5 min. The solvent was evaporated and the residue was triturated with diethyl ether and dried. This solid (approximately 6 g) was dissolved in acetone (30 ml) and then added dropwise to diethyl ether (600 ml) with rapid stirring.

The mixture was stirred for 10 min and then the solid was collected by filtration and dried in a vacuum oven at 50 ° C overnight. The solid was dissolved in deionized water (-60 ml), filtered and lyophilized, and then dried in a vacuum oven at 50 ° C for 3 hours. This gave the title material (E2) as a cream-colored solid (5.9 g) identical from the spectroscopic point of view to the preparation by method A.

image12

A solution of (2S, 5S) -7-methyl-6-oxo-2- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] -1,7-diazaspiro [4.4] nonano-1-carboxylate 5 of ferf-butyl (which can be prepared as described in description 15) (124.5 mg, 0.2500 mmol) in HCl

in dioxane (3 ml, 12 mmol) it was allowed to react at room temperature for 2 h. The solvent was evaporated and the residue was dissolved in methanol and passed through an SCX cartridge, washed with methanol and the product eluted with 0.5 M NH3 in methanol to give the free base as a clear gum ( 97 mg);

300 MHz 1H NMR 6h (CDCla) 1.83-1.89 (1H, m), 2.13-2.21 (4H, m), 2.40 (1H, m), 2.9 (1H, br .s), 2.94 (3H, s), 3.3010 3.43 (2H, m), 4.50 (1H, t), 7.31 (1H, d), 7.37 (1H, d ), 7.53 (2H, t), 7.64 (1H, d), 7.87 (1H, s), 8.64 (1H, d).

A solution of this material in DCM (2 ml) was treated with HCl in ether (0.27 ml, 0.2700 mmol) and the mixture was allowed to stand at room temperature for 2 minutes. The solvent was evaporated almost to dry completely and then diethyl ether (20 ml) was added to precipitate the product. The solid was collected by filtration and then dried in a vacuum oven overnight at 45 ° C to provide the title compound (E3) 15 (84 mg);

M / Z: 392 (M + H +).

BIOLOGICAL TESTS

The compounds of the invention were analyzed with a QPatch NaV1.7 assay.

QPatch NaV1.7 test

The HEK293-hNaV1.7 cells were grown in DMEM-F12 + 10% SBF culture medium at 37 ° C. At a confluence of 50-70%, the cells dissociated from the culture flasks and were crushed to ensure the suspension of the unicellular cells; Cell density was measured and adjusted to 2-3 x 10 6 cells / ml. Records were obtained with QPatch16x. The external solution was (in mM): NaCl, 128; KCl, 5; MgCU, 2; CaCh, 2; Glucose, 30; HEPES, 15; pH 7.3, 305-315 mOsm. After the formation of the seal and access to all cells with the internal solution (containing in mM: CsF, 135; EGTA / CsOH, 1/5; HEPES, 10; NaCl, 10; pH 7.3, 310 -320 mOsM), the voltage pulse protocols were applied. Initially, a steady state inactivation voltage protocol was used to determine the semi-maximum voltage for steady state inactivation (V1 / 2 IEE). Two constant voltages were used to determine the inhibition of the drug problem: -90 mV, where the mayona of the channels are in a closed state; and V1 / 2 IEE, where half of the channels are inactive. The currents 30 are triggered every 10 s stepwise to a membrane potential of 0 mV for 20 ms. The responses of the cumulative concentrations of four points were derived by determining the amplitude of the peak current at each concentration of the problem drug during an application of 120 s. The curves were adjusted with the Hill equation, which produced pIC50 values at the constant potentials of -90 mV and IEE V1 / 2.

 Example Number

 QP Nav1.7 -90mV pIC50 QP Nav1.7 V1 / 2 IEE pIC50

 one

 4.3 5.5

Claims (12)

1. A compound of the formula (I) which is 7-methyl-2- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] -1,7-diazaspiro [4.4] nonan-6- one: 5 image 1 or a pharmaceutically acceptable salt thereof. 10 2. A compound as defined in claim 1, wherein the compound of formula (I) is a compound according to any of formulas (Ia) - (Id): image2 image3 5 10 fifteen twenty 25 30 image4 3. A compound as defined in claim 2, wherein the compound of formula (I) is a compound of formula (la): image5 4. A compound of formula (I) as defined in claim 1, which is: (2R, 5S) -7-methyl-2- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] -1,7-diazaspiro [4.4] nonan-6-one (E1) hydrochloride (E1). 5. A compound of formula (I) as defined in claim 1, which is: (2R, 5S) -7-methyl-2- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] -1,7-diazaspiro [4.4] nonan-6-one (E2) hemisulfate hydrate. 6. A compound of formula (I) as defined in claim 1, which is: (2S, 5S) -7-methyl-2- [4- [3- (trifluoromethoxy) phenyl] -2-pyridyl] -1,7-diazaspiro [4.4] nonan-6-one (E3) hydrochloride (E3). 7. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable carriers, diluents and / or excipients. 8. A compound of formula (I) as defined in any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, for use in treatments. 9. A compound of formula (I) as defined in any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, to be used for the treatment of a disease or condition mediated by modulating the dependent sodium ionotrope channels. of voltage 10. A compound of formula (I) as defined in any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, to be used for the treatment of neuropathic pain. 11. Use of a compound of formula (I) as defined in any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of pain, inflammatory disorders, ophthalmic diseases, lung diseases , digestive tract disorders, headache, multiple sclerosis, myocardial ischemia, depression and mood disorders, schizophrenia, anxiety disorders, substance-related disorders, cognitive impairment, sleep disorders, eating disorders, autism spectrum disorders, attention deficit hyperactivity disorder, personality disorder, sexual dysfunction, impulse control disorder, bipolar disorders, nicotine-related disorders, treatable and / or preventable disorders with anticonvulsants, bladder hyperreflexia after inflammation of the bladder, neurodegenerative diseases and neurodegeneration, sclerosi s lateral amyotrophic, neuroinflammation, neurodegeneration after a stroke, cardiac arrest, pulmonary bypass, brain injury or spinal cord injury, or tinnitus. 12. A process for preparing a compound of formula (I) as defined in claim 1, comprising: (a) reacting a compound of formula (II): image6 5 or a protected derivative thereof, wherein L1 represents a suitable leaving group, such as a halogen atom (e.g., bromine) or a -O-SO2CF3 group, with a compound of formula (III): image7 wherein X represents boronic acid; (b) reduction of a compound of formula (IV): 10 or a protected derivative thereof; (c) deprotection of a protected derivative of a compound of formula (I); (d) optional formation of a pharmaceutically acceptable salt of a compound of formula (I). image8